Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists

ABSTRACT

The present invention relates to compounds that are fast dissociating dopamine 2 receptor antagonists, processes for preparing these compounds, pharmaceutical compositions comprising these compounds as an active ingredient. The compounds find utility as medicines for treating or preventing central nervous system disorders, for example schizophrenia, by exerting an antipsychotic effect without motor side effects.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/091,219 filed on Apr. 23, 2008, which is a national stage of PCTApplication No. PCT/EP2006/067696, filed Oct. 24, 2006, which claimspriority from European Patent Application No. 06101545.9, filed Feb. 10,2006; European Patent Application No. 06100209.3, filed Jan. 10, 2006;and European Patent Application No. 05110028.7, filed Oct. 26, 2005, theentire disclosures of which are hereby incorporated in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that are fast dissociatingdopamine 2 receptor antagonists, processes for preparing thesecompounds, pharmaceutical compositions comprising these compounds as anactive ingredient. The compounds find utility as medicines for treatingor preventing central nervous system disorders, for exampleschizophrenia, by exerting an antipsychotic effect without motor sideeffects.

BACKGROUND PRIOR ART

J. Med. Chem. (1999), 42 (4), 730-741 discloses6-phenyl-N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridazinamine andanalogous compounds as acetylcholinesterase inhibitors.

Farmaco, Vol. 35, no. 11, 1980, pages 951-964 discloses substitutedN-[4-piperidinyl]-2-aminopyrimidines having dopaminergic activity, i.e.most of the disclosed compounds are agonists at the dopamine D2receptor. Since none of the compounds tested antagonized the stereotypedbehavior induced by a subsequent dose of apomorphine they may also beconsidered to be devoid of dopamine receptor blocking properties. Thecompounds of the present invention differ in the presence of apyridazine instead of a pyrimidine and the unexpected finding that theyexert an antagonistic effect at the dopamine D2 receptor.

DESCRIPTION OF THE INVENTION

Schizophrenia is a severe and chronic mental illness that affectsapproximately 1% of the population. Clinical symptoms are apparentrelatively early in life, generally emerging during adolescence or earlyadulthood. The symptoms of schizophrenia are usually divided into thosedescribed as positive, including hallucinations, delusions anddisorganised thoughts and those referred to as negative, which includesocial withdrawal, diminished affect, poverty of speech and theinability to experience pleasure. In addition, schizophrenic patientsare suffering from cognitive deficits, such as impaired attention andmemory. The aetiology of the disease is still unknown, but aberrantneurotransmitter actions have been hypothesized to underlie the symptomsof schizophrenia. The dopaminergic hypothesis is one most oftenconsidered; it proposes that hyperactivity of dopamine transmission isresponsible for the positive symptoms observed in schizophrenicpatients. This hypothesis is based on the observation that dopamineenhancing drugs, such as amphetamine or cocaine, may induce psychosis,and on the correlation that exists between clinical doses ofantipsychotics and their potency in blocking dopamine D2 receptors. Allmarketed antipsychotics mediate their therapeutic efficacy againstpositive symptoms by blocking the dopamine D2 receptor. Apart from theclinical efficacy, it appears that the major side effects ofantipsychotics, such as extrapyramidal symptoms (EPS) and tardivedyskinesia, are also related to dopamine antagonism. Those debilitatingside effects appear most frequently with the typical or first generationof antipsychotic (e.g., haloperidol). They are less pronounced with theatypical or second generation of antipsychotic (e.g., risperidone,olanzapine) and even virtually absent with clozapine, which isconsidered the prototypical atypical antipsychotic. Among the differenttheories proposed for explaining the lower incidence of EPS observedwith atypical antipsychotics, the one that has caught a lot of attentionduring the last fifteen years, is the multireceptor hypothesis. Itfollows from receptor binding studies showing that many atypicalantipsychotics interact with various other neurotransmitter receptors inaddition to dopamine D2 receptors, in particular with the serotonin5-HT2 receptors, whereas typical antipsychotic like haloperidol bindmore selectively to the D2 receptors. This theory has been challenged inrecent years because all major atypical antipsychotics fully occupy theserotonin 5-HT2 receptors at clinically relevant dosages but stilldiffer in inducing motor side-effects. As an alternative to themultireceptor hypothesis, Kapur and Seeman (“Does fast dissociation fromthe dopamine D2 receptor explain the action of atypical antipsychotics?:A new hypothesis”, Am. J. Psychiatry 2001, 158:3 p. 360-369) haveproposed that atypical antipsychotics can be distinguished from typicalantipsychotics by the rates at which they dissociate from dopamine D2receptors. The fast dissociation from the D2 receptor would make anantipsychotic more accommodating of physiological dopamine transmission,permitting an antipsychotic effect without motor side effects. Thishypothesis is particularly convincing when one considers clozapine andquetiapine. These two drugs have the fastest rate of dissociation fromdopamine D2 receptors and they carry the lowest risk of inducing EPS inhumans. Conversely, typical antipsychotics associated with a highprevalence of EPS, are the slowest dissociating dopamine D2 receptorantagonists. Therefore, identifying new drugs based on their rate ofdissociation from the D2 receptor appears as a valid strategy to providenew atypical antipsychotics. An additional goal is to combine fastdissociating properties with selectivity for dopamine D2 receptors. Themultiple receptor profile of current atypical antipsychotics is thoughtto be the cause of other side effects, such as weight gain and diabetes.Searching for selective D2 antagonists has been ignored as an approachfor some time but it is our belief that using more selective compoundsin clinic may reduce the occurrence of metabolic disorders associatedwith current atypical antipsychotic drugs.

It is the object of the present invention to provide novel compoundsthat are fast dissociating dopamine D2 receptor antagonists which havean advantageous pharmacological profile as explained hereinbefore, inparticular reduced motor side effects, and moderate or negligibleinteractions with other receptors resulting in reduced risk ofdeveloping metabolic disorders.

This goal is achieved by the present novel compounds according toFormula (I):

the pharmaceutically acceptable salts, hydrates and solvates thereof,and stereoisomeric forms thereof, wherein

-   -   R is hydrogen or C₁₋₆alkyl;    -   R¹ is phenyl; phenyl substituted with 1, 2 or 3 substituents        each independently selected from the group consisting of        hydrogen, halo, cyano, C₁₋₄alkyl, C₁₋₄alkyloxy,        perfluoroC₁₋₄alkyl, diC₁₋₄alkylamino; thienyl; thienyl        substituted with 1 or 2 substituents selected from the group        consisting of halo and    -   C₁₋₄alkyl; C₃₋₈cycloalkyl; or C₅₋₇cycloalkenyl;    -   R² is hydrogen or C₁₋₆alkyl;    -   R³ is halo, C₁₋₄alkyl or perfluoroC₁₋₄alkyl; and    -   R⁴ and R⁵ each independently are hydrogen or halo.

The compounds according to the invention are fast dissociating D₂receptor antagonists, an activity not attributed to any of the6-phenyl-N-[4-piperidinyl]-3-pyridazinamine derivatives of J. Med. Chem.(1999), 42 (4), 730-741, nor any of the substitutedN-[4-piperidinyl]-2-aminopyrimidines of Farmaco, Vol. 35, no. 11, 1980,pages 951-964.

This property renders the compounds according to the inventionespecially suitable for use as a medicine in the treatment or preventionof schizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder, psychotic disorder not otherwisespecified; psychosis associated with dementia; major depressivedisorder, dysthymic disorder, premenstrual dysphoric disorder,depressive disorder not otherwise specified, Bipolar I disorder, bipolarII disorder, cyclothymic disorder, bipolar disorder not otherwisespecified, mood disorder due to a general medical condition,substance-induced mood disorder, mood disorder not otherwise specified;generalized anxiety disorder, obsessive-compulsive disorder, panicdisorder, acute stress disorder, post-traumatic stress disorder; mentalretardation; pervasive developmental disorders; attention deficitdisorders, attention-deficit/hyperactivity disorder, disruptivebehaviour disorders; personality disorder of the paranoid type,personality disorder of the schizoid type, personality disorder of theschizotypical type; tic disorders, Tourette's syndrome; substancedependence; substance abuse; substance withdrawal; trichotillomania.

A skilled person can make a selection of compounds based on theexperimental data provided in the Experimental Part hereinafter. Anyselection of compounds is embraced within this invention.

For example, the invention particularly relates to compounds of Formula(I), wherein R³ is trifluoromethyl; and R, R⁴ and R⁵ are hydrogen.

Other interesting compounds of Formula (I) are those wherein R² ishydrogen or methyl.

Of particular interest are compounds of Formula (I) wherein R¹ is4-fluorophenyl or 3,4-difluorophenyl.

Amongst the compounds of Formula (I), the most interesting areN-[1-(4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine,andN-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine.

Throughout this application, the term “C₁₋₄alkyl” when used alone andwhen used in combinations such as “C₁₋₄alkyloxy”, “perfluoroC₁₋₄alkyl”,“diC₁₋₄alkylamino”, includes, for example, methyl, ethyl, propyl, butyl,1-methylpropyl, 1,1-dimethylethyl, the term; “C₁₋₆alkyl” includesmethyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyland hexyl; “perfluoroC₁₋₄alkyl” includes for example trifluoromethyl,pentafluoro ethyl, heptafluoropropyl and nonafluorobutyl; C₃₋₈cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl; C₅₋₇cycloalkenyl includes cyclopentenyl, cyclohexenyland cycloheptenyl.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salts forms that thecompounds according to Formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to Formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid and phosphoric acid; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,mandelic acid, fumaric acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylicacid, pamoic acid and mandelic acid. Conversely, said salts forms can beconverted into the free forms by treatment with an appropriate base.

The term solvates refers to hydrates and alcoholates which the compoundsof Formula (I) may form.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of Formula (I) areembraced within the scope of this invention.

The compounds of Formula (I) as prepared in the processes describedbelow may be synthesized in the form of racemic mixtures of enantiomersthat can be separated from one another following art-known resolutionprocedures. The racemic compounds of Formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of Formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Pharmacology

In order to find antipsychotic compounds active against positivesymptoms and having an improved safety profile (low EPS incidence and nometabolic disorders), we have screened for compounds selectivelyinteracting with the dopamine D2 receptor and dissociating fast fromthis receptor. Compounds were first screened for their D2 affinity in abinding assay using [³H]spiperone and human D2L receptor cell membranes.The compounds showing an IC₅₀ less than 1 μM were tested in an indirectassay adapted from a method published by Josee E. Leysen and WalterGommeren, Journal of Receptor Research, 1984, 4(7), 817-845, to evaluatetheir rate of dissociation.

The compounds were further screened in a panel of more than 50 commonG-protein coupled receptors (CEREP) and found to have a clean profile,that is to have low affinity for the tested receptors.

Some of the compounds have been further tested in in vivo models such asthe “Apomorphine induced emesis test in Dogs” and the “Apomorphine testin rats” and found to be orally bio-available.

In view of the aforementioned pharmacology of the compounds of Formula(I), it follows that they are suitable for use as a medicine, inparticular for use as an antipsychotic. More especially the compoundsare suitable for use as a medicine in the treatment or prevention ofschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder, psychotic disorder not otherwisespecified; psychosis associated with dementia; major depressivedisorder, dysthymic disorder, premenstrual dysphoric disorder,depressive disorder not otherwise specified, Bipolar I disorder, bipolarII disorder, cyclothymic disorder, bipolar disorder not otherwisespecified, mood disorder due to a general medical condition,substance-induced mood disorder, mood disorder not otherwise specified;generalized anxiety disorder, obsessive-compulsive disorder, panicdisorder, acute stress disorder, post-traumatic stress disorder; mentalretardation; pervasive developmental disorders; attention deficitdisorders, attention-deficit/hyperactivity disorder, disruptivebehaviour disorders; personality disorder of the paranoid type,personality disorder of the schizoid type, personality disorder of theschizotypical type; tic disorders, Tourette's syndrome; substancedependence; substance abuse; substance withdrawal; trichotillomania.

To optimize treatment of patients suffering from a disorder as mentionedin the foregoing paragraph, the compounds of Formula (I) may beadministered together with other psychotropic compounds. Thus, in thecase of schizophrenia, negative and cognitive symptoms may be targeted.

The present invention also provides a method of treating warm-bloodedanimals suffering from such disorders, said method comprising thesystemic administration of a therapeutic amount of a compound of Formula(I) effective in treating the above described disorders.

The present invention also relates to the use of compounds of Formula(I) as defined hereinabove for the manufacture of a medicament, inparticular an antipsychotic medicament, more especially a medicine inthe treatment or prevention of schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, substance-induced psychotic disorder, psychotic disorder nototherwise specified; psychosis associated with dementia; majordepressive disorder, dysthymic disorder, premenstrual dysphoricdisorder, depressive disorder not otherwise specified, Bipolar Idisorder, bipolar II disorder, cyclothymic disorder, bipolar disordernot otherwise specified, mood disorder due to a general medicalcondition, substance-induced mood disorder, mood disorder not otherwisespecified; generalized anxiety disorder, obsessive-compulsive disorder,panic disorder, acute stress disorder, post-traumatic stress disorder;mental retardation; pervasive developmental disorders; attention deficitdisorders, attention-deficit/hyperactivity disorder, disruptivebehaviour disorders; personality disorder of the paranoid type,personality disorder of the schizoid type, personality disorder of theschizotypical type; tic disorders, Tourette's syndrome; substancedependence; substance abuse; substance withdrawal; trichotillomania.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.01 mg/kg to about 10 mg/kg body weight, more preferably from about0.05 mg/kg to about 1 mg/kg body weight.

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to Formula (I).

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. The compoundsaccording to the invention, in particular the compounds according toFormula (I), a pharmaceutically acceptable acid or base addition saltthereof, a stereochemically isomeric form thereof, an N-oxide formthereof and a prodrug thereof, or any subgroup or combination thereofmay be formulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, in particular, for administration orally,rectally, percutaneously, by parenteral injection or by inhalation. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof Formula (I) may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters oflong chain fatty acids and mixtures of these and other oils. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations that are intended to be converted, shortlybefore use, to liquid form preparations. In the compositions suitablefor percutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. Acid or base addition salts ofcompounds of Formula (I) due to their increased water solubility overthe corresponding base or acid form, are more suitable in thepreparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Since the compounds according to the invention are potent orallyadministrable compounds, pharmaceutical compositions comprising saidcompounds for administration orally are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds accordingto the invention in pharmaceutical compositions.

Preparation

Compounds of formula (I),

where R, R¹, R², R³, R⁴ and R⁵ are as defined before, were prepared byreacting an intermediate of formula (II),

where R², R³, R⁴ and R⁵ are as defined in formula (I), with anintermediate of formula R₁—C(═O)—R, where R and R¹ are as definedbefore, in the presence of a suitable reducing agent such as sodiumtriacetoxyborohydride, a suitable acid catalyst, such as acetic acid, ina suitable reaction inert solvent such as 1,2-dichloroethane.

Intermediates of formula (II), were prepared by reacting a protectedpiperidine derivative of formula (IV),

where P represents a suitable protecting group, such astert-butyloxycarbonyl, with a 3-chloropyridazine of formula (V),

in the presence of a suitable catalyst, such as potassium iodide, undersuitable reaction conditions, such as in a melt, followed bydeprotection of the protecting group in intermediate (VI)

under suitable condition, such as hydrochloric acid in methanol for thetert-butyloxycarbonyl group.

Intermediates of formula (V) are available either commercially or areprepared by procedures similar to those described in the chemicalliterature (for R³═CF₃, see Tetrahedron, 1999, 55 (52), 15067-15070).

Compounds of formula (I) can also be prepared reacting a3-chloropyridazine of formula (V) with a piperidine derivative offormula (VII)

in the presence of a suitable base such as diisopropylamine in asuitable solvent such as an alkanol, e.g. 1-butanol, at an elevatedtemperature.

Intermediates of formula (VII) were prepared by reacting4,4-ethylenedioxypiperidine (VIII) with an intermediate of formulaR₁—C(═O)—R, in the presence of a suitable reducing agent such as sodiumtriacetoxyborohydride, a suitable acid catalyst such as acetic acid, ina suitable reaction inert solvent such as 1,2-dichloroethane.

The resulting intermediate of formula (IX)

was deprotected by treatment with an acid such as hydrochloric acid togive an intermediate of formula (X)

which was then reacted with an amine of formula R²—NH₂ (XI), in thepresence of a suitable reducing agent such as hydrogen, a suitablecatalyst, such as palladium on carbon in a suitable reaction inertsolvent such as ethanol.

The intermediates of formula (II) wherein R⁵ represents chloro wereprepared by reacting a piperidine of formula (XII)

wherein L represents a leaving group such as tosyl, with a pyridazine offormula (XIII)

wherein R³ is as defined before, in the presence of a suitable base suchas sodium hydride in an aprotic solvent such as dimethylformamide,followed by deprotection of the protecting group in the intermediate offormula (VI) under suitable conditions, such as hydrochloric acid inmethanol for the tert-butyloxycarbonyl group.

The intermediates of formula (XIII) can be prepared from pyridazines offormula (V) by amination and subsequent halogenation.

Experimental Part

Chemistry

Final purification of Examples (E1-E45) was carried out either by columnchromatography on silica gel using the eluent described or by reversedphase preparative HPLC on a Hyperprep RP 18 BDS (Shandon) (8 μm, 200 mm,250 g) column. Three mobile phases (mobile phase A: 90% 0.5%ammoniumacetate+10% acetonitrile; mobile phase B: methanol; mobile phaseC: acetonitrile) were used to run a gradient method starting with 75% Aand 25% B with a flow rate of 40 ml/min, hold for 0.5 minutes at thesame conditions followed with an increase of the flow rate to 80 ml/minin 0.01 minutes to 50% B and 50% C in 41 minutes, to 100% C in 20minutes and hold these conditions for 4 minutes.

¹H spectra were recorded on a Bruker DPX 360 spectrometer. The chemicalshifts are expressed in ppm relative to tetramethylsilane.

Description 1 tert-Butyl4-{-[6-(trifluoromethyl)pyridazin-3-yl]amino}piperidine-1-carboxylate(D1)

A mixture of 3-chloro-6-trifluoromethyl-pyridazine (4.4 g, 24.1 mmol)(prepared by a procedure similar to that described in Tetrahedron, 1999,55 (52), 15067-15070), 4-amino-1-tert-butyloxycarbonylpiperidine (9.63g, 48.1 mmol) and potassium iodide (cat.) were heated in a melt at 150°C. for 30 min. After this period, the reaction mixture was diluted withwater and extracted with dichloromethane. The organic layer wasseparated, dried and the solvent evaporated in vacuo. The crude productwas purified by chromatography (silica; 1%-4% ammonia in methanol (7M)/dichloromethane) to give D1 (7.06 g, 85%). C₁₅H₂₁F₃N₄O₂ requires 346.Found 347 (MH⁺)

Description 2 N-Piperidin-4-yl-6-(trifluormethyl)pyridazin-3-amine (D2)

A solution of D1 (7.06 g, 20.4 mmol) and hydrochloric acid/isopropanol(6N, 100 ml) in methanol (100 ml) was stirred at room temperature for 2h. After this period, solvents were evaporated in vacuo and the residuetriturated with acetonitrile. The solid product was filtered off anddried to give D2 as the di-hydrochloride salt (6.05 g, 95%). C₁₀H₁₃F₃N₄requires 246. Found 247 (MH⁺)

The di-hydrochloride salt (D2) was either used directly in thesubsequent preparation of example compounds or alternatively convertedto the free base prior to use. The free base was prepared by dissolutionof the di-hydrochloric salt in water, basifying with sodium carbonateand extracting with dichloromethane. After drying (MgSO₄), the solventswere evaporated in vacuo to give the free base (D2a).

Description 3 8-(3,4-Difluorobenzyl)-1,4-dioxa-8-azaspiro[4.5]decane(D3)

A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol),4,4-ethylenedioxy-piperidine (4.40 g, 30.9 mmol), sodiumtriacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0mmol) in dichloroethane (200 ml) was stirred at room temperature for 18h. After this period, the reaction mixture was washed with 1N sodiumhydroxide. The organic layer separated, dried (MgSO₄) and the solventsevaporated in vacuo to give D3 (7.9 g, 98%). C₁₄H₁₇F₂NO₂ requires 269.Found 270 (MH⁺)

Description 4 1-(3,4-Difluorobenzyl)piperidine-4-one (D4)

A solution of D3 (7.9 g, 29.4 mmol) in hydrochloric acid (5N, 150 ml)was heated at 50° C. for 2 h. After this period, the reaction mixturewas washed with diisopropyl ether (100 ml) and then a saturated solutionof sodium hydrogen carbonate (100 ml). The mixture was then extractedwith dichloromethane and the extracts dried (MgSO₄) and the solventsevaporated in vacuo to give D4 (5.4 g, 82%). C₁₂H₁₃F₂NO requires 225.Found 226 (MH⁺)

Description 5 1-(3,4-Difluorobenzyl)-N-methylpiperidine-4-amine (D5)

A suspension of D4 (5.4 g, 24 mmol), thiophene solution (4% indiisopropylether; 2 ml), methylamine solution (40% in water, 10 ml) and10% palladium on carbon (2 g) in methanol (150 ml) were hydrogenated atatmospheric pressure and temperature until 1 eq. (˜600 ml) of hydrogenhad been taken up. After this period, the reaction mixture was filteredand the filtrate evaporated in vacuo. The crude product was purified bycolumn chromatography (silica; 5%-10% ammonia inmethanol/dichloromethane) to give D5 (4.7 g, 81%). C₁₃H₁₈F₂N₂ requires240. Found 241 (MH⁺)

Description 6 6-Trifluoromethyl-3-pyridazinamine (D6)

A mixture of 3-chloro-6-trifluoromethyl-pyridazine (1.6 g, 8.8 mmol)(prepared by a procedure similar to that described in Tetrahedron, 1999,55 (52), 15067-15070) and ammonium hydroxide (30 ml) in THF (10 ml) washeated at 100° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for1 h. After this period, the reaction mixture was evaporated and theresidue extracted with dichloromethane. The combined extracts were dried(MgSO₄), filtered and the solvents evaporated in vacuo to give D6 (1.3g, 93%). C₅H₄F₃N₃ requires 163. Found 164 (MH⁺)

Description 7 4-Chloro-6-trifluoromethyl-3-pyridazinamine (D7)

A mixture of D6 (4.0 g, 24.5 mmol) and N-chlorosuccinimide (3.3 g, 24.5mmol) in acetonitrile (160 ml) was heated at 70° C. for 18 h. After thisperiod, the reaction was cooled to room temperature and the solventsevaporated in vacuo. The crude residue was purified by columnchromatography (silica; 3%-5% methanol/dichloromethane) to give D7 (1.6g, 33%). C₅H₃ClF₃N₃ requires 197. Found 198 (MH⁺)

Description 8 tert-butyl4-{[4-chloro-6-(trifluoromethyl)pyridazin-3-yl]amino}piperidine-1-carboxylate(D8)

To a stirred solution of D7 (1.6 g, 8.1 mmol) in dimethylformamide (50ml) at 0° C., under nitrogen, was added NaH (60% in oil; 390 mg, 8.1mmol) portionwise. The reaction mixture was stirred for 1 h., before4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester(2.9 g, 8.1 mmol), dissolved in dimethylformamide (10 ml), was addeddropwise. The reaction mixture was then heated between 80-90° C. for 6hours. After cooling to room temperature, the solvents were evaporatedin vacuo. The residue was dissolved in dichloromethane and washed withwater. The organic layer was dried (MgSO₄), filtered and the solventswere evaporated in vacuo. The crude product was purified by columnchromatography (silica gel; 3% methanol in dichloromethane) to give D8(1.1 g, 37%). C₁₅H₂₀ClF₃N₄O₂ requires 380. Found 381 (MH⁺).

Description 94-Chloro-N-piperidin-4-yl-6-(trifluoromethyl)pyridazin-3-amine (D9)

A solution of D8 (1.1 g, 2.9 mmol) and hydrochloric acid/isopropanol(6N, 20 ml) in methanol (100 ml) was stirred at room temperature for 18h. After this period, the reaction mixture was evaporated in vacuo, theresidue re-dissolved in methanol and the solution made alkaline withmethanolic ammonia. The reaction mixture was concentrated in vacuo andthe residue purified by column chromatography (silica gel; 5%-15%methanolic ammonia in dichloromethane) to give D9 (70 mg, 9%).C₁₀H₁₂ClF₃N₄ requires 280. Found 281 (MH⁺).

Example 1N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine(E1)

To a stirred solution of D2a (2.61 g, 10.6 mmol) and acetic acid (0.64g, 10.6 mmol) in dichloroethane (200 ml) was added3,4-difluorobenzaldehyde (1.52 g, 10.6 mmol) and sodiumtriacetoxyborohydride (2.24 g, 10.6 mmol) at room temperature. Afterstirring for 18 h., the reaction mixture was quenched with 1N sodiumhydroxide, the organic layer removed, dried and the solvents evaporatedin vacuo. The crude product was purified by chromatography (silica;2%-5% ammonia in methanol (7 M)/dichloromethane) to give E1 (2.39 g,61%). C₁₇H₁₇F₅N₄ requires 372. Found 373 (MH⁺); mp: 167.7-168.9° C. ¹HNMR (DMSO-D6) δ 1.50 (qd, J=11.5, 3.7 Hz, 1 H), 1.96 (br.d, J=12.4 Hz, 2H), 2.12 (td, J=11.4, 2.6 Hz, 2 H), 2.78 (br.d, J=11.3 Hz, 2 H), 3.48(s, 2 H), 3.90 (br.s, 1 H), 6.94 (d, J=9.4 Hz, 1 H), 7.13-7.19 (m, 1 H),7.32-7.42 (m, 2 H), 7.53 (br.d, J=7.3 Hz, 1 H), 7.63 (d, J=9.4 Hz, 1 H)

Example 2N-[1-(4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine(E2)

A suspension of D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g,5.32 mmol), diisopropylethylamine (1.37 g, 10.6 mmol) andtriacetoxyborohydride on resin (Argonaut Technologies; 2.2 mmol/g; 3eq.) in dichloroethane (10 ml) was stirred at room temperature for 18 h.After this period, the reaction mixture was filtered and the solventsevaporated in vacuo. The crude product was purified by chromatography(silica; 2%-6% ammonia in methanol (7 M)/dichloromethane) to give E2(0.79 g, 42%). C₁₇H₁₈F₄N₄ requires 354. Found 355 (MH⁺); mp:163.3-165.3° C. ¹H NMR (DMSO-D6) δ 1.48 (q, J=10.8 Hz, 2 H), 1.95 (br.d,J=12.5 Hz, 2 H), 2.09 (t, J=11.1 Hz, 2 H), 2.78 (br.d, J=11.3 Hz, 2 H),3.47 (s, 2 H), 3.89 (br.s, 1 H), 6.94 (d, J=9.4 Hz, 1 H), 7.15 (t, J=8.8Hz, 2 H), 7.34 (dd, J=8.3, 5.7 Hz, 2 H), 7.53 (br.d, J=7.3 Hz, 1 H),7.63 (d, J=9.4 Hz, 1 H)

Example 12N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazine-3-amine(E12)

A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine(182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol(4 ml) was heated at 190° C. in a microwave reactor (Emrys Optimizer;0-9 Barr) for 2 h. After this period, the reaction mixture wasevaporated in vacuo and the residue extracted with dichloromethane. Theorganic layer was washed with a saturated solution of sodium hydrogencarbonate, dried (MgSO₄) and the solvents evaporated in vacuo.Purification by reverse phase HPLC (conditions as previously described)gave E12 (210 mg, 54%). C₁₈H₁₉F₅N₄ requires 386. Found 387 (MH⁺). ¹H NMR(CDCl₃) δ 1.74 (br.d, J=12.0 Hz, 2 H), 1.88 (qd, J=12.0, 3.9 Hz, 2 H),2.17 (td, J=11.8, 2.5 Hz, 2 H), 2.96 (br.d, J=11.6 Hz, 2 H), 3.00 (s, 3H), 3.47 (s, 2 H), 4.85 (t, J=12.1 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H),6.99-7.05 (m, 1 H), 7.10 (dt, J=10.2, 8.1 Hz, 1 H), 7.20 (ddd, J=11.4,7.8, 2.1 Hz, 1 H), 7.46 (d, J=9.6 Hz, 1 H)

Example 16N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-chloropyridazin-3-amine (E16)

A solution of 1-(4-chlorobenzyl)-piperidin-4-yl amine (1 g, 4.45 mmol)(prepared by a procedure similar to that described in WO2001098273),3,6-dichloropyridazine (670 mg, 4.45 mmol) and sodium carbonate (940 mg,8.90 mmol) in dimethylacetamide (5 ml) was heated at 120° C. in amicrowave reactor (Emrys Optimizer; 0-9 Barr) for 40 minutes. After thisperiod, the reaction mixture was diluted with water and extracted withdichloromethane. The organic layer was dried (MgSO₄), filtered and thesolvents evaporated in vacuo. Purification by reverse phase HPLC(conditions as previously described) gave E16 (228 mg, 15%). C₁₆H₁₈Cl₂N₄requires 336. Found 337 (MH⁺). ¹H NMR (360 MHz, CDCl₃) δ1.52 (qd,J=11.5, 3.5 Hz, 2 H), 2.08 (d, J=12.5 Hz, 2 H), 2.16 (t, J=11.3 Hz, 2H), 2.82 (d, J=11.5 Hz, 2 H), 3.48 (s, 2 H), 3.77-3.87 (m, 1 H), 4.55(d, J=7.8 Hz, 1 H), 6.59 (d, J=9.3 Hz, 1 H), 7.14 (d, J=9.3 Hz, 1 H),7.25 (d, J=7.7 Hz, 2 H), 7.29 (d, J=7.7 Hz, 2 H)

Example 45(R,S)—N-[1-(3,4-difluoro-α-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine(E45)

A solution of D2a (123 mg, 0.5 mmol), 3,4-difluoroacetophenone (186 mg,1.25 mmol) and titanium isopropoxide (875 mg, 3 mmol) was stirred atroom temperature for 1 h., before ethanol (0.7 ml) was added and thereaction stirred for a further 1 h. After this period, sodiumcyanoborohydride (68 mg, 1.1 mmol) was added and the reaction stirred atroom temperature overnight. The reaction mixture was then diluted withdichloroethane (30 ml), water (1 ml) was added and the mixture stirredand then filtered. The filtrate was evaporated in vacuo and the residuewas re-dissolved in dichloromethane (30 ml), washed with 10% sodiumcarbonate solution and dried (MgSO₄). The mixture was filtered and thesolvent evaporated in vacuo. Purification by reverse phase HPLC(conditions as previously described) gave E45 (106 mg, 55%). C₁₈H₂₀F₄N₄requires 368. Found 369 (MH⁺). ¹H NMR (360 MHz, CDCl₃) δ 1.33 (d, J=6.7Hz, 3 H), 1.45-1.62 (m, 2 H), 2.00-2.08 (m, 1 H), 2.09-2.21 (m, 3 H),2.70-2.78 (m, 1 H), 2.90-3.00 (m, 1 H), 3.42 (q, J=6.7 Hz, 1 H), 3.85(br.s, 1 H), 4.97 (d, J=7.3 Hz, 1 H), 6.65 (d, J=9.3 Hz, 1 H), 6.99-7.05(m, 1 H), 7.09 (dt, J=10.1, 8.2 Hz, 1 H), 7.18 (ddd, J=11.7, 7.8, 2.1Hz, 1 H), 7.42 (d, J=9.3 Hz, 1 H)

The following examples (E3-E11) were prepared from D2 or D2a and thecorresponding benzaldehyde by a procedure similar to that described inExamples 1 and 2. Examples (E13-E14) were prepared from thecorresponding benzaldehyde by a procedure similar to that described inExample 12.

      Example

      R²       M. Wt       MH+ E1 

H 372 373 E2 

H 354 355 E3 

H 370 371 E4 

H 404 405 E5 

H 354 355 E6 

H 390 391 E7 

H 328 329 E8 

H 354 355 E9 

H 388 389 E10

H 388 389 E11

H 372 373 E12

CH₃ 386 387 E13

CH₃ 418 419 E14

CH₃ 342 343

The following Examples (E15-E38) were prepared by procedures similar tothose described in Descriptions 1-5 and Examples 1, 2, 12 and 16.

      Example

      R²       M. Wt       MH+ E15

H 302 303 E16

H 336 337 E17

CH₃ 316 317 E18

CH₃ 352 353 E19

CH₃ 348 349 E20

CH₃ 352 353 E21

CH₃ 412 413 E22

CH₃ 418 419 E23

CH₃ 402 403 E24

CH₃ 402 403 E25

CH₃ 384 385 E26

CH₃ 344 345 E27

CH₃ 358 359 E28

CH₃ 402 403 E29

CH₃ 348 349 E30

CH₃ 400 401 E31

CH₃ 350 351 E32

CH₃ 308 309 E33

CH₃ 320 321 E34

CH₃ 320 321 E35

CH₃ 370 371 E36

CH₃ 400 401 E37

CH₃ 348 349 E38

CH₃ 359 360 E39

CH₃ 336 337

The following Example (E40) was prepared by procedures similar to thosedescribed in Descriptions 1-5 and Examples 1, 2 and 12.

      Example

      R²       M. Wt       MH+ E40

CH₃ 364 365

The following Examples (E41-E45) were prepared by procedures similar tothose described in Descriptions 1-9 and Examples 1, 2, 12, 16 and 45.

      Example

      R       R⁵       M. Wt       MH+ E41

H H 384 385 E42

H H 372 373 E43

H Cl 406 407 E44

CH₃ H 368 369 E45

CH₃ H 386 287

The following names refer to the Example Numbers:

-   N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E1)-   N-[1-(4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E2)-   N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E3)-   N-[1-(3-trifluormethylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E4)-   N-[1-(3-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E5)-   N-[1-(3,4,5-trifluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E6)-   N-[1-(cyclopentylmethyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E7)-   N-[1-(2-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E8)-   N-[1-(4-chloro-3-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E9)-   N-[1-(3-chloro-4-fluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E10)-   N-[1-(3,5-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E11)-   N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine    (E12)-   N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine    (E13)-   N-[1-(cyclopentylmethyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine    (E14)-   N-[1-(4-chlorobenzyl)piperidin-4-yl]-6-chloropyridazin-3-amine (E16)-   N-(1-benzylpiperidin-4-yl)-N-methyl-6-chloropyridazin-3-amine (E17)-   N-[1-(3,5-difluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E18)-   N-[1-(2-fluoro-5-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E19)-   N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E20)-   N-[1-(3-bromo-4-fluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E21)-   N-[1-(4-chloro-3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E22)-   N-[1-(3-fluoro-5-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E23)-   N-[1-(2-fluoro-5-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E24)-   N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E25)-   N-[1-(2,5-dimethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E26)-   N-[1-(2,4,5-trimethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E27)-   N-[1-(4-fluoro-3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E28)-   N-[1-(4-fluoro-3-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E29)-   N-[1-(5-bromothiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E30)-   N-[1-(4,5-dimethylthiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E31)-   N-[1-(cyclopentylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E32)-   N-[1-(1-cyclohex-1-en-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E33)-   N-[1-(1-cyclohex-3-en-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E34)-   N-[1-(3,4,5-trifluorobenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E35)-   N-[1-(4-bromothiophen-2-ylmethyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E36)-   N-[1-(3-fluoro-6-methylbenzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E37)-   N-[1-(3-dimethlyamino-benzyl)piperidin-4-yl]-N-methyl-6-chloropyridazin-3-amine    (E38)-   N-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]-N-methyl-6-methylpyridazin-3-amine    (E40)-   N-[1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E41)-   N-[1-(2,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E42)-   N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)-4-chloro-pyridazin-3-amine    (E43)-   N-[1-(4-fluoro-α-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E44)-   N-[1-(3,4-difluoro-α-methylbenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine    (E45)    Pharmacology    In vitro Binding Affinity for Human D2_(L) Receptor

Frozen membranes of human Dopamine D2_(L) receptor-transfected CHO cellswere thawed, briefly homogenised using an Ultra-Turrax T25 homogeniserand diluted in Tris-HCl assay buffer containing NaCl, CaCl₂, MgCl₂, KCl(50, 120, 2, 1, and 5 mM respectively, adjusted to pH 7.7 with HCl) toan appropriate protein concentration optimised for specific andnon-specific binding. Radioligand [³H]Spiperone (NEN, specific activity˜70 Ci/mmol) was diluted in assay buffer at a concentration of 2 nmol/L.Prepared radioligand (50 μl), along with 50 μl of either the 10% DMSOcontrol, Butaclamol (10⁻⁶ mol/l final concentration), or compound ofinterest, was then incubated (30 min, 37° C.) with 400 μl of theprepared membrane solution. Membrane-bound activity was filtered througha Packard Filtermate harvester onto GF/B Unifilterplates and washed withice-cold Tris-HCl buffer (50 mM; pH 7.7; 6×0.5 ml). Filters were allowedto dry before adding scintillation fluid and counting in a Topcountscintillation counter. Percentage specific bound and competition bindingcurves were calculated using S-Plus software (Insightful). All compoundshad a pIC₅₀ values>6.0 except E8, E25, E41, E42, E44 and E45(pIC₅₀>5.2).

Fast Dissociation

Compounds showing an IC₅₀ superior to 1 μM were tested in an indirectassay adapted from a method published by Josee E. Leysen and WalterGommeren, Journal of Receptor Research, 1984, 4(7), 817-845, to evaluatetheir rate of dissociation. Compounds at a concentration of 4 timestheir IC₅₀ were first incubated for one hour with human D2L receptorcell membranes in a volume of 2 ml at 25° C., then filtered overglass-fibre filter under suction using a 40 well multividor. Immediatelyafter, the vacuum was released. 0.4 ml of pre-warmed buffer (25° C.)containing 1 nM [³H]spiperone was added on the filter for 5 minutes. Theincubation was stopped by initiating the vacuum and immediate rinsingwith 2×5 ml of ice-cold buffer. The filter-bound radioactivity wasmeasured in a liquid scintillation spectrometer. The principle of theassay is based on the assumption that the faster a compound dissociatesfrom the D2 receptor, the faster [³H]spiperone binds to the D2 receptor.For example, when D2 receptors are incubated with clozapine at theconcentration of 1850 nM (4×IC₅₀), [³H]spiperone binding is equivalentto 60-70% of its total binding capacity (measured in absence of drug)after 5 min incubation on filter. When incubated with otherantipsychotics, [³H]spiperone binding varies between 20 and 50%. Sinceclozapine was included in each filtration run, tested compounds wereconsidered fast dissociating D2 antagonists if they were dissociating asfast or faster than clozapine. All measured compounds had a dissociationrate faster than that of clozapine, i.e. >50%.

The invention claimed is:
 1. A method of treating a patient withpsychosis selected from the group consisting of schizophrenia,schizophreniform disorder, schizoaffective disorder comprisingadministering to said patient a therapeutically effective amount totreat psychosis of a compound of formula (I)

or a pharmaceutically acceptable salt, hydrate or solvate thereof, or astereoisomeric form thereof, wherein R is hydrogen or C₁₋₆alkyl; R¹ isphenyl; phenyl substituted with 1, 2 or 3 substituents eachindependently selected from the group consisting of hydrogen, halo,cyano, C₁₋₄alkyl, C₁₋₄alkyloxy, perfluoroC₁₋₄alkyl, diC₁₋₄alkylamino;thienyl; thienyl substituted with 1 or 2 substituents selected from thegroup consisting of halo and C₁₋₄alkyl; C₃₋₈cycloalkyl; orC₅₋₇cycloalkenyl; R² is hydrogen or C₁₋₆alkyl; R³ is halo, C₁₋₄alkyl orperfluoroC₁₋₄alkyl; and R⁴ and R⁵ each independently are hydrogen orhalo.
 2. The method of claim 1 wherein the psychosis is schizophrenia.